In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

Abstract

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that pairedlike homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca 2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na + channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.

In Silico Assessment of Class I Antiarrhythmic Drugs Effects on Pitx2-induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

“…(1) Populations of models based on two human atrial AP models are able to mimic a wide range of inter-subject variability in human atrial AP properties as exhibited in a set of AP measurements from over 379 SR and AF patients. (2) Pitx2-induced remodelling (as reported in [36]) predicts abbreviated APD90 and increased dVdtmax at the cellular level, and increased CV and shortened WL at the tissue level in SR versus AF conditions, as reported in experimental studies [17,59] (Table 2). (3) AP biomarkers (namely APD90 and dVdtmax) are correlated in both SR and AF cardiomyocytes created with the Bai et al and the Grandi et al models.…”

“…Previous experiments in atrial cardiomyocytes of Tbx5-deleted mice showed reduced Pitx2 and sodium channel genes although reduced Pitx2 without alterations in Tbx5 caused an increase in sodium channel genes [17]. Based on these data on remodelled INa due to impaired Pitx2, Pitx2-induced AF model was developed and predicted an increase in action potential amplitude and maximum upstroke velocity [36]. Consistent with these findings, our simulations in the Pitx2-induced AF population of models show that increased upstroke velocity is determined by INa and is positively correlated with INa (Figure 4).…”

“…Class I AADs used in AF include flecainide, disopyramide, quinidine and propafenone [35]. The pharmacological effects of flecainide in Pitx2-induced AF were investigated by using a multi-scale computational model and simulated results demonstrated that flecainide is effective for the treatment of Pitx2-induced AF patients by preventing spontaneous calcium release [36]. However, the efficacy of other Class I AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling remains elusive.…”

“…Although the efficacy of disopyramide, quinidine, and propafenone on human atrial pathoelectrophysiology associated with hERG-linked short QT syndrome has been investigated using a multi-scale computational model [37], mechanisms by which short QT mutations promote AF may be different from that underlying Pitx2-induced AF [27][28][29][30][31][32]36]. Also, both clinical [34] and theoretical [36] studies of pharmacotherapy for Pitx2-induced AF often ignored inter-subject variability in atrial electrophysiology properties.…”

“…Although the efficacy of disopyramide, quinidine, and propafenone on human atrial pathoelectrophysiology associated with hERG-linked short QT syndrome has been investigated using a multi-scale computational model [37], mechanisms by which short QT mutations promote AF may be different from that underlying Pitx2-induced AF [27][28][29][30][31][32]36]. Also, both clinical [34] and theoretical [36] studies of pharmacotherapy for Pitx2-induced AF often ignored inter-subject variability in atrial electrophysiology properties. Population-based computational approaches that can capture key disease conditions have proven valuable for understanding inter-subject variability in electrophysiological properties [38][39][40] and cardiotoxicity [41][42][43][44][45][46][47][48][49][50][51][52][53].…”